Sex differences exist in multiple phases of opioid dependence (OD) including acquisition, escalation, addiction, withdrawal, relapse, and treatment response. Overall, men are more likely to become OD than women, although women tend to progress and develop medical or social consequences faster, have more difficulty discontinuing use, and more vulnerable to relapse. Thus, determining sex-specific factors underlying OD is critical for optimizing prevention and treatment strategies for men and women with OD. Identifying relevant genetic factors holds particular promise. Although studies have reported sex-specific heritability of OD and different association results for men and women for some candidate genes in OD, the results to date are meagre, and sex-specific genome wide association studies (GWAS) on OD have never been reported. We will use rigorous statistical approaches to identify sex-specific genetic risk factors for OD. We have a well-characterized substance-dependent (SD) cohort for African and European Americans with GWAS and exome-array data that can be analyzed and leveraged with publically available genetic and genomics data. This large SD cohort has been assessed using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) instrument. In this proposal, OD defined by DSM criterion count will be the targeted trait for analysis. The overall goal of this administrative supplement proposal is to analyze the genetic data we have collected for women and men to identify most effectively sex-specific genetic variants.